Accumulating evidence suggests that early intervention (particularly with novel antipsychotics) may improve the long-term course of schizophrenia. While clinicians are routinely using novel antipsychotic drugs for patients within the first episode of schizophrenia, and large-scale investigations of novel antipsychotics in first episode patients are underway, the novel drug clozapine (CLOZ) is not used clinically or in most research studies in patients because of Its side effects and the practical difficulties with its use. The notion behind our proposed research, however, is that CLOZ may be relatively safe and particularly helpful for first episode patients who are comorbid for cannabis use disorder (CUD). These comorbid patients, comprising approximately 50% of first episode patients, have a poor outcome, especially when cannabis use continues over time. A number of lines of evidence provide support for a study of CLOZ in this population: (a) preliminary data suggest that CLOZ (but not risperidone [RISP] -or olanzapine) decreases substance use in patients with schizophrenia; (b) preliminary data suggest that CLOZ (but not RISP or olanzapine) is more efficacious for first episode patients than typical antipsychotics; (c) preliminary data suggest that CLOZ decreases suicide rates in chronic schizophrenia; and (d) established data indicate CLOZ's unique efficacy in poor-outcome patients. The PI's recently published neurobiologic formulation to help explain the beneficial effects of CLOZ on comorbid substance use provides further support for this application. In this revised application (under 'Pilot Effectiveness Trials for Mental Health'), the PI and colleagues begin a line of investigation to study the comparative effects of CLOZ and RISP in patients within their first episode of schizophrenia who are comorbid for CUD. The overarching hypothesis is that CLOZ (compared to RISP) will decrease cannabis and other substance use and will also improve the outcome of these patients. The clinical implication of this hypothesis is that CLOZ may have a clear therapeutic advantage for such patients (and may even be lifesaving) and may well be the drug of choice for them. In this pilot application, we will gather short- and long term preliminary efficacy data (and effect sizes), and further assess the risks and benefits of CLOZ in this population, to provide the basis for a large-scale effectiveness trial to compare the effects of treatment with CLOZ or RISP on cannabis and other substance use, global functioning, clinical symptoms, quality of life, and neurocognitive functioning, as well as on cost effectiveness of treatment in first episode patients with schizophrenia who are comorbid for CUD.